Johnson & Johnson's Prostate Drug Fails Clinical Trial

In order to succeed, the AA-302 trial had to increase progression-free survival (or PFS) and overall survival. Just one or the other wasn't enough.

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MINYANVILLE ORIGINAL That's a different headline than you probably have been reading since Saturday. You've been reading how Johnson & Johnson's (JNJ) prostate cancer drug Zytiga (scientific name: abiraterone) aced a trial in men with metastatic, castrate-resistant prostate cancer (mCRPC) who had not yet received chemotherapy. You've probably been reading the so-called "AA-302" trial proves it is the best thing since sliced bread.

Well, the drug certainly has a benefit for patients. But the AA-302 trial was a failure. Don't take my word for it. Look up the presentations on the American Society of Clinical Oncology (ASCO) website (you may have to pay) and listen to Dr. Susan Halabi's discussion of the data. She called it a failure, too.

In order to succeed, the AA-302 trial had to increase progression-free survival (or PFS) and overall survival. Just one or the other wasn't enough. Those increases had to be statistically significant. Johnson & Johnson and the press have focused on PFS, as that endpoint was positive.

Overall survival was not statistically significant (p=0.0097 versus required p=0.0008). I freely acknowledge this is splitting statistical hairs. But what the FDA's oncology division does best is split hairs. Provenge demonstrated a survival advantage in 2007 and an advisory panel said it should be approved. The FDA said the survival advantage wasn't the primary endpoint and turned it down. Roche-Genentech (RHHBY) provided great T-DM1 data in third-line breast cancer, but the FDA turned them down because the patients hadn't received a chemotherapy that nobody uses at that disease stage. Amgen (AMGN) had a PFS benefit in breast cancer, but the FDA turned them down because there was no survival advantage and there were side effects.

Splitting hairs is what the FDA does, and there are more hairs to split here then just the survival statistics. This AA-302 trial was downright strange.

Most patients were off drug by 13.8 months into the trial. Yet the survival curves don't separate until nearly 18 months into the trial. That's pretty much unprecedented in this disease stage. In the Provenge IMPACT trial, the curves separate after six months. Patients in the docetaxel chemotherapy trial (TAX-327) who had minimally symptomatic disease also saw their curves separate after about six months. The survival curves in the post-chemotherapy "AA-301" trial of Zytiga separated inside three months.

It takes 18 months for the Zytiga curves to separate. By that time, 20% of the men in the trial were dead. Translated, this means 20% of the men in the Zytiga trial were dead before the drug ever had a chance to improve their survival. Contrast this to about 5% of the men in the Provenge trial and 3-5% of the men in the docetaxel trial.

To be sure, Zytiga has some other benefits. It reduces PSA for most patients, helps with pain in some patients, and shrinks tumors in a minority of patients. But for this disease stage, the FDA's advisory panels have clearly said overall survival is necessary for approval.

Zytiga also isn't cheap. Most patients in the trial received 15 cycles of drug. At $5,495/cycle that's $82,425 (not including the cost of prednisone and all the testing necessary to avoid serious side effects). That $82,425 is spent and gone five months before you ever see any survival benefit and 20% of patients will spend that and see NO survival benefit.

When Johnson & Johnson unblinded the trial in March, it allowed patients on the control arm to receive Zytiga. This will make it more difficult to demonstrate a survival benefit. It won't be impossible, as Provenge proved with 65% of its control arm receiving a modestly active version of Provenge. But it is not a slam dunk. Dr. Halabi thinks the trial will still be statistically significant at the final analysis and, frankly, so do I.

But that still leaves this weird survival curve and the 18-month delay before any survival benefit is seen.

Notably, Johnson & Johnson plans to file for approval in the mCRPC, pre-chemo indication in the next couple of months. The FDA won't have final survival data when it is making its initial decision. The FDA will only have a failed trial with overall survival still not statistically significant.

I fully expect the FDA will ask an advisory panel for help. Key opinion leaders in the prostate cancer oncology space are clearly not happy with Johnson & Johnson for unblinding this trial early. As noted by Dr. Halabi in her presentation, Johnson & Johnson didn't really need to wait much longer and they would have had a statistically-significant survival advantage.

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